8SBJ

Co-structure Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform complexed with brain penetrant inhibitors

Summary for 8SBJ

• Entry DOI: 10.2210/pdb8sbj/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, (2M)-7-[(3R)-3-methylmorpholin-4-yl]-5-[(3S)-3-methylmorpholin-4-yl]-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine, ... (4 entities in total)
• Functional Keywords: lipid kinase, mutant, p85, nish2, brain-penetrant, mtor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 160814.07

Authors

Knapp, M.S.,Elling, R.A.,Tang, J. (deposition date: 2023-04-03, release date: 2023-07-19, Last modification date: 2024-05-22)

Primary citation

Bonazzi, S.,Gray, A.,Thomsen, N.M.,Biag, J.,Labbe-Giguere, N.,Keaney, E.P.,Malik, H.A.,Sun, Y.,Nunez, J.,Karki, R.G.,Knapp, M.,Elling, R.,Fuller, J.,Pardee, G.,Craig, L.,Capre, K.,Salas, S.,Gorde, A.,Liang, G.,Lubicka, D.,McTighe, S.M.,Goold, C.,Liu, S.,Deng, L.,Hong, J.,Fekete, A.,Stadelmann, P.,Frieauff, W.,Elhajouji, A.,Bauer, D.,Lerchner, A.,Radetich, B.,Furet, P.,Piizzi, G.,Burdette, D.,Wilson, C.J.,Peukert, S.,Hamann, L.G.,Murphy, L.O.,Curtis, D.
Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.
J.Med.Chem., 66:9095-9119, 2023

PubMed Abstract: The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor () that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the 1 gene. However, showed the risk of genotoxicity . Through structure-activity relationship (SAR) optimization, we identified compounds and without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the 1 gene knockout model. Unfortunately, and showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

PubMed: 37399505
DOI: 10.1021/acs.jmedchem.3c00705

Experimental method

X-RAY DIFFRACTION (3.1 Å)